<p> The synthesis and characterization of folding aromatic oligoamides with reduced constraint, ion-pair associations and solvent-mediated folding of aromatic oligoureas, and oligoamides with unique conformational variations involving simple structural inversion are presented in this thesis. </p><p> Chapter 1 is a review of the foldamer field defining structural features of peptides that are desired for replication by artificial building blocks. Foldamers are characterized as either peptidomimetic or abiotic based on intrinsic properties of the building blocks utilized. Each section of peptidomimetic and abiotic foldamers demonstrates the systematic design and characterization utilized for each system, including highlights of progressive developments within the field. This leads into the early development of helical aromatic oligoamides, developed by Gong and coworkers, incorporating rotation restricting three-center hydrogen bonds imbedded in the backbone. Overall, providing the relationship between our helical aromatic oligoamides and their place in the foldamer field. </p><p> Chapter 2 presents modifications in the design of robust aromatic oligoamides to incorporate reduced hydrogen bonding constraint within the backbone. This increased flexibility was to improve protein-like folding behavior for these previously robust oligoamides. Flexibility was designed by removing aromatic side chains adjacent to the benzene residues allowing only 5-membered ring (two-center) hydrogen bonding to remain. Two variations of oligoamides were synthesized involving alternating constraint consisting of interchanging three- and two-center hydrogen bonding along the aromatic backbone, and reduced constraint with only 2-center hydrogen bonding. Folding potentials are presented utilizing a combination of circular dichroism, 1D/ 2D NMR experiments, thermal denaturation and titration experiments in varying solvent conditions. </p><p> Chapter 3 begins with an overview of past aromatic oligourea design and cationic recognition of uncyclized and cyclized aromatic tetraureas. Anionic recognition of halides with ureas observed in literature was confirmed by concentration-dependent ¹H-NMR experiments for aromatic urea dimers, similar in structure to elongated oligourea sequences. Anions were also observed to associate with oligourea trimers with similar affinities compared to their iv tetraethylammonium salt counterions, not previously observed for the dimers. Cation binding within the cavity of these trimers was confirmed by 2D NMR experiments. Correlations between 2D NMR spectra and results from concentration-dependent ¹H-NMR experiments led to the conclusion of positive cooperative association between anion and cation pairs with oligourea trimer hosts. The conformational preference of longer aromatic oligoureas, incorporating fivemembered hydrogen bonding constraining the urea-linkage, was determined to favor a <i>trans-trans</i> conformation based on urea-linkage bond rotations that were computationally derived in collaboration with Professor Eva Zurek and Daniel Miller. Longer oligoureas were confirmed to also to bind tetraethyl- and tetrabutylammonium cations by 2D NMR experiments. Folding and chain-length dependence of these longer oligoureas were characterized by circular dichroism and ¹H-NMR, confirming solvent-dependent folding and aggregation. Finally an aromatic oligourea 9mer was confirmed to favor a helical structure stabilized by dimethylformamide. </p><p> Chapter 4 presents two aromatic oligoamides with a simple inversion between their &alpha;&beta; and &beta;&alpha;-amino acid spacers which caused the individual conformational identity to differ dramatically, preventing these complementary strands to associate. A qualitative examination compared differences in structural properties by ¹H-NMR concentration-dependent, titrationdependent and temperature-dependent experiments. It was concluded that the oligoamide involving the &alpha;&beta; spacer preferred to fold upon itself, generating a stable &beta;-turn which was confirmed by 2D NMR. The oligoamide incorporating a &beta;&alpha; spacer self-dimerized with significant conformational interconversion, requiring the oligoamide to be examined at cryogenic temperatures to derive a specific conformation. In collaboration with Professor Eva Zurek and Daniel Miller, conformations derived from NOEs observed by 2D NMR experiments were examined computationally. A favored model paired with atomic distances calculated from optimized NOEs concluded the refinement of a specific conformation regarding this oligoamide.</p><p>

Three Cu complexes varying in oxidation state from +1 to +3 were prepared from CuII starting materials and the hexafluoro-α-cumyl alkoxide ligand. These species include a targeted CuII tris-alkoxide, K[Cu(OC(C6H5)(CF3)2)3] (3); a trimeric Cu(I) complex, {K(18C6)}[K2{Cu(OC(C6H5)(CF3)2)2}3] (4); and a rare organocuprate CuIII complex, {K(18C6)}[Cu(OC(C6H4)(CF3)2)2] (5), which is stable at RT and has formed via ortho¬ metalation of two C-H bonds present. The three complexes have been structurally characterized, and 4 and 5 were studied using NMR spectroscopy to gain insight into the mechanism of formation. Using the bidentate perfluoropinacolate ligand (pinF)2-, four CuI complexes of the form K[(R3P)Cu(pinF)] or {K(18C6)}[(R3P)Cu(pinF)], with PR3 = PPh3 (9, 11) or PCy3 (10, 12) have been synthesized, and structurally and spectroscopically characterized. Complexes 9-12 reduce O2 at -78°C to form a symmetric trinuclear {Cu3O2} species, SyTpinF, which has been characterized by EPR, cryo-MS, and stopped-flow spectroscopy. Kinetic formation and decay constants in conjunction with DFT calculations revealed evidence for an asymmetric, trimeric, intermediate species, AsTpinF, which forms prior to SyTpinF. The trimeric core catalytically oxidizes para-hydroquinone to benzoquinone as a form of oxidase chemistry. The CuII complex, K2[Cu(pinF)2] (14), has been evaluated for stability at reducing potentials in organic and aqueous media by cyclic voltammetry and UV-vis. The electrochemical reactivity of 14 was examined in basic conditions, which showed that 14 is a precatalyst for the reduction of the NOx substrates NO3- and NO2-. The catalytic onset potential of NOx reduction coincides with the reduction of a transient CuI species to Cu0 on the glassy carbon based electrode. Controlled potential electrolysis with concomitant 15N-NMR studies have shown near quantitative reduction of NO3- to NO2- and NH4+ products or reduction of NO2- to NH4+.

Interfaces play a crucial role in a variety of physical, chemical, and biological phenomena. Due to the unique local environment, chemical and physical properties observed at the interface are different than in bulk media. This work exploits the highly selective surface layer sensitivity of the second-order phenomenon vibrational sum-frequency generation (SFG) spectroscopy to learn about interfacial chemistry and structure. The surface pKa of substituted benzoic acids and short-chain carboxylic acids are found by SFG spectroscopy and surface tension measurements. Measured surface pKa values are greater than bulk solution values and are attributed to increased surface proton concentrations. Stronger van der Waals interactions are also found to increase pKa. Anomalously large carbonyl stretching SFG intensities are found in a narrow pH range and provide evidence for a cooperative surface adsorption effect between p-methyl benzoic acid and its conjugate base. In SFG studies of poly(N-isopropylacrylamide) (pNIPAM), Hofmeister anion effects are observed for the amide I band. Furthermore, SFG spectra reveal two distinct pNIPAM amide I bands. One peak is centered at 1625 cm-1, consistent with bulk FTIR studies, and a second peak is observed at 1665 cm-1, blue shifted by 40 cm-1. The “bulk-like” peak (1625 cm-1) arises from fully solvated pNIPAM molecules located just below the interfacial layer and is enhanced in the presence of chaotropic anions. The blue shifted peak is attributed to decreased water solvation of pNIPAM molecules at the uppermost surface layer. An odd-even effect is observed in the SFG spectra of n-alkanethiolate self-assembled monolayers (SAMs) on Au and Ag surfaces depending on surface roughness. Odd-even oscillations in SFG signal amplitudes and linewidths were observed for spectra derived from alkyl thiols with either odd or even numbers of carbons for SAMs on flat surfaces (RMS roughness = 0.40 nm), but not on rougher surfaces (RMS roughness = 2.38 nm). This effect is attributed to differences in terminal methyl group orientation for odd or even n. This work demonstrates the capability of SFG spectroscopy to be an effective tool for determining surface number density, equilibrium constants, and molecular orientation for molecules at the interface.

The development of new procedures for the production of biologically and industrially relevant compounds still remains a big challenge in chemistry. The biaryl motif is ubiquitous among a wide range of compounds of industrial importance. For example, the biaryl skeleton is found in molecular switches and motors, agrochemicals or medicines such as antifungal, anticancer, antibiotics, anti-inflammatory treatments. These properties make the biaryl functionality a highly desirable synthetic target, for both commercial and research purposes. In this context, C-H arylation has been acknowledged as a useful alternative to traditional cross-couplings, replacing the organometallic coupling partner by a non-prefunctionalised substrate in the reaction with a haloarene. Approaches for the development of Ru-catalysed C-H arylation methodologies are presented herein. The introduction provides a general overview about different strategies employed in metalcatalysed direct C-H arylation methods. The rational behind selectivity and reactivity are also thoroughly discussed. The second chapter describes studies on the C-H activation of perfluorinated arenes by Ru(II)-species. The synthesis of unprecedented aryl rutyhenium complexes and mechanistic considerations on the metalation of the arene are presented. In the last part of the second chapter the development of a bis-cationic rutehium(II) complex able to catalyse direct C-H arylation of electron-poor arenes with bromoarenes in the absence of any directing group is described. A complete mechanistic analysis, along with the scope of the methodology, is therefore given.

Thesis: Ph. D. in Organic Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2015. / Cataloged from PDF version of thesis. Vita. / Includes bibliographical references. / Chapter 1 A mild, versatile, and convenient method for the efficient oxytrifluoromethylation of unactivated alkenes based on a copper-catalyzed ligand-assisted difunctionalization strategy has been developed. This method provides access to a variety of classes of synthetically useful CF3-containing building blocks from simple starting materials. Chapter 2 A method for the efficient enantioselective oxytrifluoromethylation of alkenes has been developed using a copper catalyst system inspired by the ligand dependence observed in the racemic reaction. Mechanistic studies are consistent with a metal-catalyzed redox radical addition mechanism, in which a C-0 bond is formed via the copper-mediated enantioselective trapping of a prochiral alkyl radical intermediate derived from the initial trifluoromethyl radical addition. Chapter 3 A general and versatile method for the catalytic enantioselective oxyfunctionalization of alkenes has been developed based on a key Cu-mediated enantioselective C-0 bond forming process of prochiral alkyl radical intermediates. A wide range of radicals were found to participate this type of reaction, including azidyl, arylsulfonyl, aryl, acyloxyl and alkyl radicals. This method provides rapid access to a broad spectrum of interesting enantiomerically enriched lactones through tandem C-N/C-O, C-S/C-O, C-Cary/aIkyI/C-O or C-O/C-O bond formation, in good yields and enantiomeric excesses with good functional group compatibility. / by Rong Zhu. / Ph. D. in Organic Chemistry

Thesis: Ph. D. in Organic Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2015. / Cataloged from PDF version of thesis. Vita. / Includes bibliographical references. / I. The Development of Epipolythiodiketopiperazine (ETP) Syntheses Epipolythiodiketopiperazine (ETP) alkaloids represent a structurally complex and biologically potent class of secondary fungal metabolites and these molecules have been known since the 1930s. The biological activity of these molecules is quite potent and the modes of toxicity possessed by these agents involve the generation of reactive oxygen species (ROS) and direct manipulation of target proteins. The biosynthesis of these compounds has been the subject of active study and we have presented our own hypothesis how theses molecules are synthesized by fungi. Efforts to synthesize these alkaloids have been known since the late 1960 to early 1970s and all have highlighted the need to install the requisite disulfide bridge at a late-stage. The ETP motif is known to be notoriously sensitive as it is reactive towards bases and Lewis acids, and in photochemical and redox reactions. II. Development of ETP Syntheses for the Application of the Total Synthesis of (+)- bionectin A The concise and efficient total synthesis of (+)-bionectin A is described. Our approach to these natural products features a new and scalable method for erythro-[beta]- hydroxytryptophan amino acid synthesis and a new mercaptan reagent for the epipolythiodiketopiperazine (ETP) synthesis that can be unraveled under very mild conditions. The development of this new reagent was accomplished after exploring the acid promoted incorporation of different alkyl thiols into diketopiperazine diol substrates. III. Concise Total Synthesis of (+)-Luteoalbusin A The first total synthesis of (+)-luteoalbusin A is described. Our concise and enantioselective synthesis began from the simple starting materials L-alanine and Ltryptophan. Transformations central to our route include a highly regioselective Friedel- Crafts indolization that can be performed on multi-gram scale, as well as a highly diastereoselective oxidation and thiolation. Moreover, this divergent synthesis features a common aminothioisobutyryl intermediate that can be utilized to construct (+)- luteoalbusin A. The spectral data obtained from the synthetic samples confirmed the assigned structure for this natural product. / by Timothy C. Adams. / Ph. D. in Organic Chemistry

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 2018. / Cataloged from PDF version of thesis. / Includes bibliographical references. / Endoplasmic reticulum-associated degradation (ERAD) is essential for protein quality control both during stress and at steady state. We found that an E2 ubiquitin-conjugating enzyme UBC6e contributes to a new layer of homeostatic control, in which ERAD activity itself is regulated post-transcriptionally and independently of the unfolded protein response. Ablation of UBC6e causes up-regulation of active ERAD enhancers and increases clearance not only of terminally misfolded substrates, but also of wild-type glycoproteins that fold comparatively slowly. Tuning of ERAD component level involves a mechanism that is likely distinct from the conventional ERAD by Hrdl/SEL1L complex. To better understand how UBC6e is controlled, we developed VHH05, which associates with UBC6e with a low nanomolar dissociation constant. VHH05 enhances enzymatic activity of UBC6e by binding to a gateway helix on UBC6e (168-186). As the phosphorylation site S184 is on this gateway loop, we propose that stress-induced phosphorylation of UBC6e allows binding of a cytosolic factor that enhances UBC6e activity similarly to VHH05. We further characterized the binding of VHH05 to UBC6e to identify a 14mer binding epitope QADQEAKELARQIS. This epitope was translated into a 6e-tag recognized by VHH05. VHH05 specifically retrieves 6e-tagged proteins from a complex lysate mixture. VHH05 sortagged with biotin or fluorophores can stain 6e-tagged protein in an immunoblot and in FACS. VHH05 recognizes 6e-tag in the reducing environment of the cytosol and can be used to target tagged proteins to selective locations in the cell. To study the ubiquitination machinery in live cells, we used CellSqueeze technology to deliver epitope-tagged ubiquitin (Ub) to HeLa cells. The delivered Ub molecules are readily utilized in the cell. Furthermore, kinetics of Ub incorporation is much faster in lysates than in squeezed cells. Further experiments using E2s pre-loaded with Ub in the presence of El inhibition showed that E2-Ubs are also utilized faster in lysates than in squeezed cells. We hope to use this technology to identify the contribution of E2s to substrate selectivity and characterize interactions between E3s and E2-Ubs. / by Jingjing Ling. / Ph. D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, February 2005. / Vita. / Includes bibliographical references. / One of the major goals in molecule engineering is the creation of molecule- or polymer- based devices that mimic the integrated functions of their macroscopic (and often inorganic) counterparts. Because of their unique photophysical and/or redox properties, supramolecular systems and conjugated polymers (CPs) have emerged as the ideal candidates for such applications. This dissertation details the design and synthesis of various CPs with pendant supramolecular complexes. The marriage of these two materials should yield complex and unique properties that are not accessible from single-molecule systems. Chapter One is an introduction on conjugated polymers and their properties. The ease of synthetic modifications, coupled with their unique transport properties make CPs very desirable for the design of sensitive chemosensors. The incorporation of rotaxane moieties to poly(p-phenyleneethynylene)s will be described in Chapter Two. By design, the rotaxane groups behave as molecular recognition elements for the detection of small molecules. In addition, these bulky scaffolds prevent polymer aggregation. We turn our focus to the rotaxane monomers in Chapter Three. We investigate the photoinduced charge transfer interactions between donor and acceptor pairs within the rotaxane scaffold and examine the parameters that facilitate these interactions. Chapter Four describes our effort to encapsulate electroactive polymers using these bulky groups. As expected, insulation of conducting polymer severely limits the polymer's charge transport and leads to a dramatic decrease in the polymer's bulk conductivity. The tetrahedral binding site in the rotaxane group allows complexation of redox active metal ions. / (cont.) These ions provide critical interconnects and mediate interchain charge hopping. Chapter Five describes another conducting organic-metal hybrid system, wherein two distinct conducting polymers are configured in a cross-linked network held together by a rotaxane architecture. Anion interactions with the redox active metal ions modulate the redox properties of the metal centers, thereby affecting the polymer's conductivity. / by Phoebe Hoi-Ying Kwan. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 2014. / Cataloged from PDF version of thesis. Vita. / Includes bibliographical references. / CHAPTER I. Rhodium-Catalyzed Epoxide-Opening Cascades: Formal Synthesis of (-)-Brevisin [chemical formula inserted] [Rh(CO)₂Cl]₂ was found to be an effective catalyst for endo-selective cyclizations and cascades of epoxy-(E)-enoate alcohols, thus enabling the synthesis of oxepanes and oxepanecontaining polyethers from di- and trisubstituted epoxides. Syntheses of the ABC and EF ring systems of (-)-brevisin via all endo-diepoxide-opening cascades using this method constitute a formal total synthesis and demonstrate the utility of this methodology in the context of the synthesis of marine ladder polyether natural products CHAPTER II. Synthetic Studies Toward Hemibrevetoxin B [chemical formula inserted] We report progress toward a biomimetic epoxide-opening cascade of the marine ladder polyether hemibrevetoxin B. Model studies demonstrate the ability of both [Rh(CO)₂Cl]₂ and cationic Rh(I) species to override the typical exo-directing of proximal methyl groups on in epoxy alcohol cyclizations for the synthesis of oxepanes. The synthesis of tri-epoxide cascade precursor and initial investigations toward an epoxide-opening cascade are described as well. / by Kurt W. Armbrust. / Ph. D.

Thesis: Ph. D. in Inorganic Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2016. / Cataloged from PDF version of thesis. / Includes bibliographical references. / The low-temperature and cost-effective oxidation of carbon monoxide to carbon dioxide remains a fundamental challenge in heterogeneous catalysis that would enable a diverse range of technologies for electrochemical storage and respiratory health. The development of new catalysts is often driven by high-throughput screening and many of the resulting compounds are mixed-phase, which obscures a rigorous identification of active sites and mechanisms at play for catalysis. In this thesis, the preparation of substituted ceria nanoparticles is described to bring about a fundamental understanding of the structure of the active sites, mechanism and design descriptors for CO oxidation on ceria-based catalysts. Monodisperse, single-phase nanoparticles of late first-row transition-metal-substituted ceria (MyCe₁.yO₂-x, M = Mn, Fe, Co, Ni and Cu) are prepared from the controlled pyrolysis of heterobimetallic precursors in amine surfactant solutions. By means of kinetic analyses, X-ray absorption spectroscopy (XAS) and transmission electron microscopy (TEM), the active site for CO oxidation catalysis is identified as atomically-dispersed, square-planar M³+ and M²+ moieties substituted into the surface of the ceria lattice. The introduction of CuO does not contribute to the catalytic activity of CuyCe₁.yO₂-x, lending support to the hypothesis that the substituted ceria itself is responsible for the catalytic rate enhancement in mixed-phased catalysts like CuO/CeO₂ Under oxygen-rich conditions, the kinetic parameters for CO oxidation are consistent with lattice oxygen from the dispersed copper sites contributing directly to the oxidation of CO in the rate-determining step. In-situ X-ray photoelectron spectroscopy (XPS) and FTIR studies indicate that adsorbed CO can be directly oxidized to CO₂ in the absence of gaseous O₂, while in-situ XAS confirms that electron transfer is localized to the copper sites. XAS studies demonstrate that the reversible reducibility of dispersed copper ions is a contributing factor for the special catalytic activity of CuO/CeO₂ catalysts. The oxygen-ion vacancy formation energy is introduced as an activity descriptor to rationalize trends in the catalytic activities measured for MyCe₁-yO₂-x nanoparticles that span over three orders of magnitude. As such, the DFT-calculated vacancy formation energy serves to guide in the rational design of catalysts through computational, rather than experimental, screening of candidate compounds for CO oxidation catalysis. / by Joseph Spanjaard Elias. / Ph. D. in Inorganic Chemistry